Trifluridine and Tipiracil) Tablets, for Oral Use • Embryo-Fetal Toxicity: Fetal Harm Can Occur

Home , Tipiracil, Trifluridine

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ______WARNINGS AND PRECAUTIONS ______LONSURF safely and effectively. See full prescribing information for • Severe Myelosuppression: Obtain complete blood counts prior to and on LONSURF. Day 15 of each cycle. Reduce dose and/or hold LONSURF as clinically indicated. (5.1) LONSURF (trifluridine and tipiracil) tablets, for oral use • Embryo-Fetal Toxicity: Fetal harm can occur. Advise women of Initial U.S. Approval: 2015 potential risk to a fetus. (5.2)

______INDICATIONS AND USAGE ______ADVERSE REACTIONS ______LONSURF is a combination of trifluridine, a nucleoside metabolic inhibitor, The most common adverse reaction (≥10%) are anemia, neutropenia, and tipiracil, a thymidine phosphorylase inhibitor, indicated for the treatment asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, of patients with metastatic colorectal cancer who have been previously treated vomiting, abdominal pain, and pyrexia. (6.1) with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. To report SUSPECTED ADVERSE REACTIONS, contact Taiho (1) Oncology, Inc. at 1-844-878-2446 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ______DOSAGE AND ADMINISTRATION • Recommended dose: 35 mg/m2/dose orally twice daily on Days 1 ______USE IN SPECIFIC POPULATIONS ______through 5 and Days 8 through 12 of each 28-day cycle. (2.1) • Lactation: Do not breastfeed. (8.2) • Take LONSURF within 1 hour after completion of morning and evening • Geriatric Use: Grade 3 or 4 neutropenia and thrombocytopenia and meals. (2.1) Grade 3 anemia occurred more commonly in patients 65 years old or older who received LONSURF. (8.5) ______DOSAGE FORMS AND STRENGTHS • Renal Impairment: Patients with moderate renal impairment may require Tablets: dose modifications for increased toxicity. (8.7) • 15 mg trifluridine/6.14 mg tipiracil (3) • 20 mg trifluridine/8.19 mg tipiracil (3) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling ______CONTRAINDICATIONS Revised: 09/2015 None. (4)

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE 8.8 Ethnicity 2 DOSAGE AND ADMINISTRATION 10 OVERDOSAGE 2.1 Recommended Dose 11 DESCRIPTION 2.2 Dose Modifications 12 CLINICAL PHARMACOLOGY 3 DOSAGE FORMS AND STRENGTHS 12.1 Mechanism of Action 4 CONTRAINDICATIONS 12.2 Pharmacodynamics 5 WARNINGS AND PRECAUTIONS 12.3 Pharmacokinetics 5.1 Severe Myelosuppression 13 NONCLINICAL TOXICOLOGY 5.2 Embryo-Fetal Toxicity 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 6 ADVERSE REACTIONS 14 CLINICAL STUDIES 6.1 Clinical Trials Experience 14.1 Colorectal Cancer 7 DRUG INTERACTIONS 15 REFERENCES 8 USE IN SPECIFIC POPULATIONS 16 HOW SUPPLIED/STORAGE AND HANDLING 8.1 Pregnancy 16.1 How Supplied 8.2 Lactation 16.2 Storage and Handling 8.3 Females and Males of Reproductive Potential 17 PATIENT COUNSELING INFORMATION 8.4 Pediatric Use 8.5 Geriatric Use *Sections or subsections omitted from the full prescribing information 8.6 Hepatic Impairment are not listed. 8.7 Renal Impairment

Reference ID: 3823053 FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE LONSURF is indicated for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose The recommended starting dose of LONSURF is 35 mg/m2 up to a maximum of 80 mg per dose (based on the trifluridine component) orally twice daily within one hour of completion of morning and evening meals on Days 1 through 5 and Days 8 through 12 of each 28-day cycle until disease progression or unacceptable toxicity. Round dose to the nearest 5 mg increment. Do not take additional doses to make up for missed or held doses. LONSURF is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

2.2 Dose Modifications Obtain complete blood cell counts prior to and on Day 15 of each cycle. Do no initiate the cycle of LONSURF until: • Absolute neutrophil count (ANC) is greater than or equal to 1,500/mm3 or febrile neutropenia is resolved • Platelets are greater than or equal to 75,000/mm3 • Grade 3 or 4 non-hematological adverse reactions are resolved to Grade 0 or 1 Within a treatment cycle, withhold LONSURF for any of the following: • Absolute neutrophil count (ANC) less than 500/mm3 or febrile neutropenia • Platelets less than 50,000/mm3 • Grade 3 or 4 non-hematological adverse reactions

After recovery, resume LONSURF after reducing the dose by 5 mg/m2/dose from the previous dose level, if the following occur: • Febrile neutropenia • Uncomplicated Grade 4 neutropenia (which has recovered to greater than or equal to 1,500/mm3) or thrombocytopenia (which has recovered to greater than or equal to 75,000/mm3) that results in more than 1 week delay in start of next cycle • Non-hematologic Grade 3 or Grade 4 adverse reaction except for Grade 3 nausea and/or vomiting controlled by antiemetic therapy or Grade 3 diarrhea responsive to antidiarrheal medication

Reference ID: 3823053 A maximum of 3 dose reductions are permitted to a minimum dose of 20 mg/m2 twice daily. Do not escalate LONSURF dose after it has been reduced.

3 DOSAGE FORMS AND STRENGTHS LONSURF (15 mg trifluridine/6.14 mg tipiracil) is a white, biconvex, round, film-coated tablet, imprinted with ‘15’ on one side, and ‘102’ and ‘15 mg’ on the other side, in gray ink. LONSURF (20 mg trifluridine/8.19 mg tipiracil) is a pale red, biconvex, round, film-coated tablet, imprinted with ‘20’ on one side, and ‘102’ and ‘20 mg’ on the other side, in gray ink.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS

5.1 Severe Myelosuppression In Study 1, LONSURF caused severe and life-threatening myelosuppression (Grade 3-4) consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%) and febrile neutropenia (3.8%). One patient (0.2%) died due to neutropenic infection. In Study 1, 9.4% of LONSURF- treated patients received granulocyte-colony stimulating factors. Obtain complete blood counts prior to and on Day 15 of each cycle of LONSURF and more frequently as clinically indicated. Withhold LONSURF for febrile neutropenia, Grade 4 neutropenia, or platelets less than 50,000/mm3. Upon recovery resume LONSURF at a reduced dose. [see Dosage and Administration (2.2)]

5.2 Embryo-Fetal Toxicity Based on animal studies and its mechanism of action, LONSURF can cause fetal harm when administered to a pregnant woman. Trifluridine/tipiracil caused embryo-fetal lethality and embryo-fetal toxicity in pregnant rats when orally administered during gestation at dose levels resulting in exposures lower than those achieved at the recommended dose of 35 mg/m2 twice daily. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LONSURF. [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)]

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in detail in other sections of the labeling:

• Severe Myelosuppression [see Warnings and Precautions (5.1)]

Reference ID: 3823053 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below are from Study 1, a randomized (2:1), double-blind, placebo-controlled trial in which 533 patients (median age 63 years; 61% men; 57% White, 35% Asian, 1% Black) with previously treated metastatic colorectal cancer received LONSURF as a single agent at a dose of 35 mg/m2/dose administered twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. The mean duration of LONSURF therapy was 12.7 weeks. The most common adverse drug reactions or laboratory abnormalities (all Grades and greater than or equal to 10% in incidence) in patients treated with LONSURF at a rate that exceeds the rate in patients receiving placebo were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia. In Study 1, 3.6% of patients discontinued LONSURF for an adverse event and 13.7% of patients required a dose reduction. The most common adverse reactions leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea.

Reference ID: 3823053 Table 1 Per Patient Incidence of Adverse Drug Reactions (≥5%) in Study 1 Occurring More Commonly (>2%) than in Patients Receiving Placebo.

LONSURF Placebo Adverse Reactions (N=533) (N=265)

All Grades Grades 3-4* All Grades Grades 3-4*

Gastrointestinal disorders

Nausea 48% 2% 24% 1%

Diarrhea 32% 3% 12% <1%

Vomiting 28% 2% 14% <1%

Abdominal pain 21% 2% 18% 4%

Stomatitis 8% <1% 6% 0%

General disorders and administration site conditions

Asthenia/fatigue 52% 7% 35% 9%

Pyrexia 19% 1% 14% <1%

Metabolism and nutrition disorders

Decreased appetite 39% 4% 29% 5%

Nervous system disorders

Dysgeusia 7% 0% 2% 0%

Skin and subcutaneous tissue disorders

Alopecia 7% 0% 1% 0%

*No Grade 4 definition for nausea, abdominal pain, or fatigue in National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.

Reference ID: 3823053 Table 2 Laboratory Test Abnormalities

LONSURF Placebo (N=533*) (N=265*)

Laboratory Parameter Grade† Grade†

All 3 4 All 3 4 % % % % % %

Blood and lymphatic system disorders

Anemia‡ 77 18 N/A# 33 3 N/A

Neutropenia 67 27 11 1 0 0

Thrombocytopenia 42 5 1 8 <1 <1 * % based on number of patients with post-baseline samples, which may be less than 533 (LONSURF) or 265 (placebo) † Common Terminology Criteria for Adverse Events (CTCAE), v4.03 ‡ Anemia: No Grade 4 definition for these laboratory parameters in CTCAE, v4.03 # One Grade 4 anemia adverse reaction based on clinical criteria was reported

In Study 1, infections occurred more frequently in LONSURF-treated patients (27%) compared to those receiving placebo (15%). The most commonly reported infections which occurred more frequently in LONSURF-treated patients were nasopharyngitis (4% versus 2%), and urinary tract infections (4% versus 2%). In Study 1, pulmonary emboli occurred more frequently in LONSURF-treatment patients (2%) compared to no patients on placebo. Additional Clinical Experience Interstitial lung disease was reported in fifteen (0.2%) patients, three of which were fatal, among approximately 7,000 patients exposed to LONSURF in clinical studies and clinical practice settings in Asia.

7 DRUG INTERACTIONS No pharmacokinetic drug-drug interaction studies have been conducted with LONSURF.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Risk Summary

Reference ID: 3823053 Based on animal data and its mechanism of action, LONSURF can cause fetal harm. LONSURF caused embryo-fetal lethality and embryo-fetal toxicity in pregnant rats when given during gestation at doses resulting in exposures lower than or similar to exposures at the recommended dose in humans. [see Data] There are no available data on LONSURF exposure in pregnant women. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Trifluridine/tipiracil was administered orally once daily to female rats during organogenesis at dose levels of 15, 50, and 150 mg/kg [trifluridine (FTD) equivalent]. Decrease fetal weight was observed at FTD doses greater than or equal to 50 mg/kg (approximately 0.33 times the exposure at the clinical dose of 35 mg/m2 twice daily). At the FTD dose of 150 mg/kg (approximately 0.92 times the FTD exposure at the clinical dose of 35 mg/m2 twice daily) embryolethality and structural anomalies (kinked tail, cleft palate, ectrodactyly, anasarca, alterations in great vessels, and skeletal anomalies) were observed.

8.2 Lactation Risk Summary It is not known whether LONSURF or its metabolites are present in human milk. In nursing rats, trifluridine and tipiracil or their metabolites were present in breast milk. There are no data to assess the effects of LONSURF or its metabolites on the breastfed infant or the effects on milk production. Because of the potential for serious adverse reactions in breastfeeding infants, advise women not to breastfeed during treatment with LONSURF and for one day following the final dose. Data Radioactivity was excreted in the milk of nursing rats dosed with trifluridine/tipiracil containing 14C-FTD or 14C-tipiracil (TPI). Levels of FTD-derived radioactivity were as high as approximately 50% of the exposure in maternal plasma an hour after dosing with trifluridine/tipiracil and were approximately the same as those in maternal plasma for up to 12 hours following dosing. Exposure to TPI-derived radioactivity was higher in milk than in maternal plasma beginning 2 hours after dosing and continuing for at least 12 hours following administration of trifuridine/tipiracil.

8.3 Females and Males of Reproductive Potential Contraception Females LONSURF can cause fetal harm when administered to a pregnant woman. [see Use in Specific Populations (8.1)] Advise females of reproductive potential to use effective contraception during treatment. Males 7

Reference ID: 3823053 Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with LONSURF and for a at least 3 months after the final dose. [see Nonclinical Toxicology (13.1)]

8.4 Pediatric Use Safety and effectiveness of LONSURF in pediatric patients have not been established. Animal Data Dental toxicity including whitening, breakage, and malocclusion (degeneration and disarrangement in the ameloblasts, papillary layer cells and odontoblasts) were observed in rats treated with trifluridine/tipiracil at doses greater than or equal to 50 mg/kg (approximately 0.33 times the exposure at the clinical dose of 35 mg/m2 twice daily).

8.5 Geriatric Use In Study 1, 533 patients received LONSURF; 44% were 65 years of age or over, while 7% were 75 and over. No overall differences in effectiveness were observed in patients 65 or older versus younger patients, and no adjustment is recommended for the starting dose of LONSURF based on age. Patients 65 years of age or older who received LONSURF had a higher incidence of the following compared to patients younger than 65 years: Grade 3 or 4 neutropenia (48% vs 30%), Grade 3 anemia (26% vs 12%, and Grade 3 or 4 thrombocytopenia (9% vs 2%).

8.6 Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of LONSURF. No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin (TB) less than or equal to the upper limit of normal (ULN) and AST greater than ULN or TB less than 1 to 1.5 times ULN and any AST). Patients with moderate (TB greater than 1.5 to 3 times ULN and any AST) or severe (TB greater than 3 times ULN and any AST) hepatic impairment were not enrolled in Study 1. [see Clinical Pharmacology (12.3)]

8.7 Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of LONSURF. In Study 1, patients with moderate renal impairment (CLcr = 30 to 59 mL/min, n= 47) had a higher incidence (difference of at least 5%) of ≥ Grade 3 adverse events, serious adverse events, and dose delays and reductions compared to patients with normal renal function (CLcr ≥ 90 mL/min, n= 306) or patients with mild renal impairment (CLcr = 60 to 89 mL/min, n= 178). No dose adjustment to the starting dose of LONSURF is recommended in patients with mild or moderate renal impairment (CLcr of 30 to 89 mL/min); however patients with moderate renal impairment may require dose modification for increased toxicity. No patients with severe renal impairment (CLcr < 30 mL/min) were enrolled in Study 1. [see Clinical Pharmacology (12.3)]

Reference ID: 3823053 8.8 Ethnicity There were no clinically meaningful differences in Study 1 between Western and Asian subgroups with respect to overall incidence of adverse events or ≥ Grade 3 adverse events in either the LONSURF or placebo groups.

10 OVERDOSAGE The highest dose of LONSURF administered in clinical studies was 180 mg/m2 per day. There is no known antidote for LONSURF overdosage.

11 DESCRIPTION LONSURF contains trifluridine and tipiracil hydrochloride at a molar ratio of 1:0.5. Trifluridine Trifluridine, an antineoplastic thymidine-based nucleoside analogue, is described chemically as 2’-deoxy-5-(trifluoromethyl) uridine, and has the following structural formula: O

CF3 HN

O N HO O

Trifluridine has a molecular formula C10 H11 F3N2O5 and a molecular weight of 296.20. Trifluridine is a white crystalline powder, soluble in water, ethanol, 0.01 mol/L hydrochloric acid, 0.01 mol/L sodium hydroxide solution; freely soluble in methanol, acetone; sparingly soluble in 2-propanol, acetonitrile; slightly soluble in diethyl ether; and very slightly soluble in isopropyl ether.

Tipiracil hydrochloride Tipiracil hydrochloride, a thymidine phosphorylase inhibitor, is described chemically as 5 chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione monohydrochloride or 2,4(1H,3H)-Pyrimidinedione, 5-chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-, hydrochloride (1:1), and has the following structural formula:

Reference ID: 3823053 HN N H N O ･ HCl

NH Cl O

Tipiracil hydrochloride has a molecular formula C 9H11 ClN4O2•HCl and a molecular weight of 279.12. Tipiracil hydrochloride is a white crystalline powder, soluble in water, 0.01 mol/L hydrochloric acid, and 0.01 mol/L sodium hydroxide; slightly soluble in methanol; very slightly soluble in ethanol; and practically insoluble in acetonitrile, 2-propanol, acetone, diisopropyl ether, and diethyl ether. LONSURF Tablet (15 mg trifluridine/6.14 mg tipiracil) Each film-coated tablet of LONSURF, for oral use, contains 15 mg of trifluridine and 6.14 mg of tipiracil equivalent to 7.065 mg of tipiracil hydrochloride as active ingredients. LONSURF tablets contain the following inactive ingredients: lactose monohydrate, pregelatinized starch, stearic acid, hypromellose, polyethylene glycol, titanium dioxide, and magnesium stearate. LONSURF Tablet (20 mg trifluridine/8.19 mg tipiracil) Each film-coated tablet of LONSURF, for oral use, contains 20 mg of trifluridine and 8.19 mg of tipiracil equivalent to 9.420 mg of tipiracil hydrochloride as active ingredients. LONSURF tablets contain the following inactive ingredients: lactose monohydrate, pregelatinized starch, stearic acid, hypromellose, polyethylene glycol, titanium dioxide, ferric oxide, and magnesium stearate. Both film-coated tablets (LONSURF 15 mg/6.14 mg and 20 mg/8.19 mg) are imprinted with ink containing shellac, ferric oxide red, ferric oxide yellow, titanium dioxide, FD&C Blue No. 2 Aluminum Lake, carnauba wax, and talc.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action LONSURF consists of a thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil, at a molar ratio 1:0.5 (weight ratio, 1:0.471). Inclusion of tipiracil increases trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase. Following uptake into cancer cells, trifluridine is incorporated into DNA, interferes with DNA synthesis and inhibits cell proliferation. Trifluridine/tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice.

12.2 Pharmacodynamics Cardiac Electrophysiology

Reference ID: 3823053 LONSURF administered to 42 patients with advanced solid tumors at the recommended dosage regimen had no large effect (i.e. > 20 ms) in the mean QTc interval when compared to placebo and no evident exposure-QT relationship was identified. Two of 42 patients (4.8%) had QTc greater than 500 msec and 1 of 42 patients (2.4%) had a QTc increase from baseline greater than 60 msec.

12.3 Pharmacokinetics After twice daily dosing of LONSURF, systemic exposure (area under the concentration curve, AUC) of trifluridine increased more than dose-proportionally over the dose range of 15 to 35 mg/m2 . After administration of LONSURF 35 mg/m2 twice daily, the mean elimination half-life (t1/2 ) of trifluridine was 1.4 hours and of tipiracil was 2.1 hours after a single dose. The mean elimination half-life at steady state of trifluridine was 2.1 hours and of tipiracil was 2.4 hours.

The accumulation of trifluridine was 3-fold for AUC 0-last and 2-fold for peak plasma concentration (Cmax ) at steady state while no accumulation was observed for tipiracil. Administration of a single dose of LONSURF containing tipiracil and trifluridine 35 mg/m2 increased the mean AUC 0-last of trifluridine by 37-fold and Cmax by 22-fold with reduced variability compared to trifluridine 35 mg/m2 alone. Absorption Following a single oral administration of LONSURF at 35 mg/m2 in patients with cancer, the mean time to peak plasma concentration (Tmax ) of trifluridine was around 2 hours.

A standardized high-fat, high-calorie meal decreased trifluridine Cmax , tipiracil Cmax and AUC by approximately 40%, but did not change trifluridine AUC compared to those in a fasting state in patients with cancer following administration of a single dose of LONSURF 35 mg/m2 . It is recommended to take LONSURF within 1 hour after completion of the morning and evening meals based on the observed correlation between the increase in the Cmax of trifluridine and the decrease in neutrophil counts. Distribution Trifluridine mainly binds to human serum albumin. The in vitro protein binding of trifluridine in human plasma is greater than 96%, independent of drug concentration and presence of tipiracil. Plasma protein binding of tipiracil is below 8%. Elimination Metabolism Trifluridine and tipiracil are not metabolized by cytochrome P450 (CYP) enzymes. Trifluridine is mainly eliminated by metabolism via thymidine phosphorylase to form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY). No other major metabolites were detected in plasma or urine. Excretion Following a single dose of LONSURF at 60 mg, the mean 48-hour cumulative urinary excretion was 1.5% for unchanged trifluridine, 19.2% for FTY, and 29.3% for unchanged tipiracil. Specific Populations Age, Sex, and Race 11

Reference ID: 3823053 Based on the population pharmacokinetic analysis, there is no clinically relevant effect of age, sex, or race (White or Asian) on the pharmacokinetics of trifluridine or tipiracil. Renal Impairment In Study 1, the estimated mean AUC of trifluridine at steady state was 31% higher in patients with mild renal impairment (CLcr = 60 to 89 mL/min, n= 38) and 43% higher in patients with moderate renal impairment (CLcr = 30 to 59 mL/min, n= 16) than that in patient with normal renal function (CLcr ≥ 90 mL/min, n= 84) based on the population pharmacokinetic analysis. The estimated mean AUC of tipiracil was 34% higher in patients with mild renal impairment and 65% higher in patients with moderate renal impairment than that in patients with normal renal function. The pharmacokinetics of trifluridine and tipiracil have not been studied in patients with severe renal impairment (CLcr < 30 mL/min) or end-stage renal disease. [see Use in Specific Populations (8.7)] Hepatic Impairment In Study 1, with data from patients with normal liver function (TB and AST less than or equal to the ULN, n=96) and patients with mild hepatic impairment (TB less than or equal to the ULN and AST greater than ULN or TB less than 1 to 1.5 times ULN and any AST, n= 42), there is no clinically relevant effect of mild hepatic impairment on the exposure of either trifluridine or tipiracil based on the population pharmacokinetic analysis. Patients with moderate (TB greater than 1.5 to 3 times ULN and any AST) or severe (TB greater than 3 time ULN and any AST) hepatic impairment were not enrolled in Study 1. The pharmacokinetics of trifluridine and tipiracil have not been studied in patients with moderate to severe hepatic impairment. [see Use in Specific Populations (8.6)] Drug Interaction Studies Trifluridine is a substrate of thymidine phosphorylase, and is not metabolized by cytochrome P450 (CYP) enzyme. Tipiracil is not metabolized in either human liver or hepatocytes. In vitro studies indicated that trifluridine, tipiracil, and FTY did not inhibit the CYP enzymes and had no inductive effect on CYP1A2, CYP2B6, or CYP3A4/5. In vitro studies indicated that trifluridine was not an inhibitor of or substrate for human uptake and efflux transporters.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies evaluating the carcinogenic potential of trifluridine/tipiracil in animals have been performed. Trifluridine/tipiracil was genotoxic in a reverse mutation test in bacteria, a chromosomal aberration test in mammalian-cultured cells, and a micronucleus test in mice. Animal studies did not indicate an effect of trifluridine/tipiracil on male fertility in rats. Dose- related increases in the corpus luteum count and implanted embryo count were observed, but female fertility was not affected.

Reference ID: 3823053 14 CLINICAL STUDIES

14.1 Colorectal Cancer Study 1 The clinical efficacy and safety of LONSURF were evaluated in an international, randomized, double-blind, placebo-controlled study conducted in patients with previously treated metastatic colorectal cancer (CRC). A total of 800 patients were randomized 2:1 to receive LONSURF (N=534) plus best supportive care (BSC) or matching placebo (N=266) plus BSC. Randomization was stratified by KRAS status (wild-type vs. mutant), time since diagnosis of first metastasis (<18 months vs. ≥ 18 months), and region (Japan vs. US, Europe and Australia). Key eligibility criteria included prior treatment with at least 2 lines of standard chemotherapy for metastatic CRC, ECOG 0-1, absence of brain metastasis, and absence of ascites requiring drainage in the past four weeks. Patients received 35 mg/m2 LONSURF or matching placebo orally twice daily after meals on Days 1 - 5 and 8 – 12 of each 28-day cycle until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall survival (OS) and an additional efficacy outcome measure was progression-free survival (PFS). The median age was 63 years, 61% were male, 58% and 35% were White and Asian respectively, and all patients had baseline ECOG Performance Status (PS) of 0 or 1. The primary site of disease was colon (62%) or rectum (38%). KRAS status was wild-type (49%) or mutant (51%) at study entry. All patients received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. All but one patient received bevacizumab, and all but two patients with KRAS wild-type tumors received panitumumab or cetuximab. [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)] A statistically significant improvement in overall survival and progression-free survival were demonstrated in patients in the LONSURF plus BSC arm compared to those who received placebo plus BSC (see Table 3 and Figure 1)

Reference ID: 3823053 Table 3 Efficacy Results LONSURF Placebo (N=534) (N=266) Overall Survival Number of deaths, N (%) 364 (68) 210 (79) Median OS (months)a [95% CI]b 7.1 [6.5, 7.8] 5.3 [4.6, 6.0] Hazard ratio [95% CI] 0.68 [0.58, 0.81] P-valuec <0.001 Progression-Free Survival Number of Progression or Death, N (%) 472 (88) 251 (94) Hazard ratio [95% CI] 0.47 (0.40, 0.55) P-valuec <0.001 a Kaplan-Meier estimates b Methodology of Brookmeyer and Crowley c Stratified log-rank test (strata: KRAS status, time since diagnosis of first metastasis, region)

Reference ID: 3823053 Figure 1 Kaplan-Meier Curves of Overall Survival

15 REFERENCES 1. “OSHA Hazardous Drugs”. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied LONSURF 15 mg/6.14 mg tablets are supplied as white, biconvex, round, film-coated tablet, imprinted with ‘15’ on one side, and ‘102’ and ’15 mg’ on the other side, in gray ink. The tablets are packaged in HDPE bottles with child resistant closures in the following presentations: • 20 count: NDC 64842-1025-1 • 40 count: NDC 64842-1025-2 • 60 count: NDC 64842-1025-3 LONSURF 20 mg/8.19 mg tablets are supplied as pale red, biconvex, round, film-coated tablet, imprinted with ‘20’ on one side, and ‘102’ and ‘20 mg’ on the other side, in gray ink. The tablets are packaged in HDPE bottles with child resistant closures in the following presentations: • 20 count: NDC 64842-1020-1 • 40 count: NDC 64842-1020-2 • 60 count: NDC 64842-1020-3

Reference ID: 3823053 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. LONSURF is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 If stored outside of original bottle, discard after 30 days.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Severe Myelosuppression: Advise the patient to immediately contact their healthcare provider if they experience signs or symptoms of infection and advise patients to keep all appointments for blood tests. [see Warnings and Precautions (5.1)] Gastrointestinal toxicity: Advise patients to contact their healthcare provider for severe or persistent nausea, vomiting, diarrhea, or abdominal pain. [see Adverse Reactions (6.1)] Administration Instructions: Advise the patient that LONSURF is available in two strengths and they may receive both strength tablets to provide the prescribed dose. Advise the patient of the importance of reading prescription labels carefully and taking the appropriate number of tablets. Advise the patient to take LONSURF within 1 hour after eating their morning and evening meals. [see Dosage and Administration (2.1)] Advise the patient that anyone else who handles their medication should wear gloves. [see References (15)] Embryo-Fetal Toxicity: Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LONSURF. [see Warnings and Precautions (5.2) and Use in Specific Populations (8.3)] Lactation: Advise women not to breastfeed during treatment with LONSURF and for one day following the final dose. [see Use in Specific Populations (8.2)]

Reference ID: 3823053 PATIENT INFORMATION LONSURF® (trifluridine and tipiracil) tablets What is the most important information I should know about LONSURF? Your healthcare provider should do blood tests before you receive LONSURF, at day 15 during treatment with LONSURF, and as needed to check your blood cell counts. LONSURF may cause serious side effects, including: Low blood counts. Low blood counts are common with LONSURF and can sometimes be severe and life-threatening. LONSURF can cause a decrease in your white blood cells, red blood cells, and platelets. Low white blood cells can make you more likely to get serious infections that could lead to death. Your healthcare provider may: • lower your dose of LONSURF or stop LONSURF if you have low white blood cell or low platelet counts.

Tell your healthcare provider right away if you get any of the following signs and symptoms of infection during treatment with LONSURF: • fever • chills • body aches See “What are the possible side effects of LONSURF?” for more information about side effects. What is LONSURF? LONSURF is a prescription medicine used to treat people with colon or rectal cancer that has spread to other parts of the body and who have been previously treated or cannot receive certain chemotherapy medicines. It is not known if LONSURF is safe and effective in children. Before you take LONSURF, tell your healthcare provider about all of your medical conditions, including if you: • have kidney problems • are pregnant or plan to become pregnant. LONSURF can harm your unborn baby. For females who can become pregnant: o You should use effective birth control during treatment with LONSURF. o Tell your healthcare provider right away if you become pregnant. For males: o You should use a condom during sex with female partners who are able to become pregnant during your treatment with LONSURF and for 3 months after your last dose of LONSURF. Tell your healthcare provider right away if your partner becomes pregnant while you are taking LONSURF. • are breastfeeding or plan to breastfeed. It is not known if LONSURF passes into breast milk. Do not breastfeed during treatment with LONSURF and for one day after your last dose of LONSURF. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should I take LONSURF? • Take LONSURF exactly as your healthcare provider tells you. LONSURF comes in two strengths. Your healthcare provider may prescribe both strengths for your prescribed dose. • Take LONSURF within 1 hour after eating your morning or evening meals. • Your caregiver should wear gloves when handling LONSURF tablets. • If you miss a dose of LONSURF, do not take additional doses to make up for the missed dose. Call your healthcare provider for instructions about what to do for a missed dose. • Wash your hands after handling the LONSURF tablets. What are the possible side effects of LONSURF? LONSURF may cause serious side effects, including: • See “What is the most important information I should know about LONSURF?” The most common side effects of LONSURF include: • tiredness • vomiting • nausea • abdominal pain • decreased appetite • fever • diarrhea Tell your healthcare provider if you have nausea, vomiting, or diarrhea that is severe or that does not go away. These are not all of the possible side effects of LONSURF. For more information, ask your healthcare provider. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Reference ID: 3823053 How should I store LONSURF? • Store LONSURF at room temperature between 68oF and 77oF (20oC and 25oC). • If you store LONSURF outside of the original bottle, throw away (dispose of) any unused LONSURF tablets after 30 days. • Talk to your healthcare provider about how to safely dispose of LONSURF. Keep LONSURF and all medicines out of the reach of children. General information about the safe and effective use of LONSURF Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use LONSURF for a condition for which it was not prescribed. Do not give LONSURF to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about LONSURF that is written for health professionals. What are the ingredients in LONSURF? Active ingredients: trifluridine and tipiracil hydrochloride Other ingredients: lactose monohydrate, pregelatinized starch, stearic acid, hypromellose, polyethylene glycol, titanium dioxide, ferric oxide (20 mg tablet only), and magnesium stearate Imprinting ink: shellac, ferric oxide red, ferric oxide yellow, titanium dioxide, FD&C Blue No. 2 Aluminum Lake, carnauba wax, and talc. Manufactured by: Taiho Pharmaceutical Co., Ltd., Japan Manufactured for: Taiho Oncology, Inc., Princeton, NJ 08540 USA LONSURF is a registered trademark of Taiho Oncology, Inc. For more information, go to www.Lonsurf.com or call 1-844-878-2446. This Patient Information has been approved by the U.S. Food and Drug Administration Issued: 09/2015

Reference ID: 3823053